The unfolded protein response (UPR) is a strategy to increase the protein folding capacity of cells and to maintain the proteostasis network (PN). If this strategy fails, unfolded proteins aggregate causing many human diseases, including diabetes, arthritis and certain cancers. Thus, molecular understanding of the UPR or PN is important to develop new approaches to prevent/reverse the protein folding diseases. Ire1, an endoplasmic reticulum (ER)-resident protein, activates the UPR from yeast to humans. Ire1 activates production of the protein Xbp1 in human cells or Hac1 in yeast cells by processing (cytoplasmic splicing)theirtranslationallyrepressedmRNAs.Hac1/Xbp1thenbindstoacis-regulatoryUPRelement (UPRE) and induces expression of folding enzymes and chaperons (e.g., yeast Kar2 or human BiP). Though Hac1 is thought to induce the Kar2 in yeast, it has been shown that the Kar2 level is significantly increased when Hac1 or Ire1 protein null strain is subjected to an ER stress. We found that the Kar2 level was decreased in the strain lacking a new UPR modulator Kin2 and remained unchanged even when the Hac1 protein level was reduced in a strain lacking the kinase Pkh1. These observations suggest that other sensors or components might activate the yeast UPR. To identify new components modulating the yeast UPR, we conducted a genetic screen with gene-deletion strains of the yeast Saccharomyces cerevisiae and found that the amount of Hac1 or UPRE-driven lacZ reporter was significantly reduced in a few strains each lacking a single protein. These proteins include Vps15 (an ortholog of human phosphoinositide-3- kinase (PI3K) regulatory subunit), Bmh2 (an ortholog of human 14-3-3 protein) and Yhr097C (a previously uncharacterized protein and hereafter referred to as Pdp2) and Cdc42 (a conserved Rho-like GTPase). These proteins (Kin2, Vps15, Bmh2, Cdc42 and Pdp2) have been shown to play important roles in distinct cellular processes, and our results reveal their novel role in the UPR. We also obtained data that provided insights on Kin2 activation, interactions among the new UPR regulators, and the involvement of Vps15 in the UPR. Here, we will test three hypotheses: (1) Cdc42 and Bmh2 bind to Kin2 releasing auto-inhibition and enabling an upstream kinase to phosphorylate/activate the Kin2 kinase domain (KD); (2) Pdp2 activates HAC1 mRNA translation by interacting with its 3?- untranslated region; and (3) Vps15 kinase augments the Hac1-mediated UPR, or alternatively promotes the UPR by phosphorylating a substrate. The insights on the fundamental mechanism of the UPR obtained from these studies in yeast will provide new avenues of investigation for the human UPR leading to the possible identification of new pathway components to target and treat protein-folding diseases.